tbuckley/cabot-search huggingface dataset:
Association between time to treatment initiation and survival in metastatic renal cell cancer: A population-based study of 5,193 cases from the California Cancer Registry (2010-2019).
Authors: David Joseph Benjamin, Anshu Shrestha, Dimitra Fellman, Arash Rezazadeh
Journal: Journal of Clinical Oncology (2023)

e16530 Background: The treatment of metastatic renal cell cancer (RCC) has changed since the approval of the first tyrosine kinase inhibitor (TKI) in 2005. Since then, combination therapy with immunotherapy and TKI is considered standard-of-care. Despite multiple drug approvals, it remains unclear whether patients should be initiated on treatment immediately (within 30 days) as opposed to delay treatment (after 30 days), and if time to initiating treatment correlates with survival. Methods: Adults aged 20 years and older with newly diagnosed metastatic RCC between 2010 and 2019 were identified through the California Cancer Registry (n = 5,193). Time to treatment was calculated as duration between date of diagnosis and date of treatment initiation, then categorized into: No treatment, treatment within 30 days, between 31-60 days, and &gt; 60 days. Association between treatment timing and overall and cancer-specific survival were assessed using Cox proportional hazard model and Fine and Gray sub-distribution hazard model accounting for competing risk. Both models included patient and baseline clinical characteristics. Results: 47.6% (n = 2,470) of patients received treatment with 30 days of diagnosis, while 24.3% received treatment between days 31-60 from diagnosis and 14.1% started treatment at 61 days or after from the time of diagnosis. After adjusting for all covariates, patients who received treatment at 61 days or later were less likely to experience mortality from cancer (HR 0.76, 95% 0.69-0.84, p &lt; 0.0001) compared to those who started treatment within 30 days. Patients who started treatment between days 31-60 from diagnosis were also less likely to experience mortality from cancer (HR 0.82, 95% CI 0.76-0.89, p &lt; 0.001). There were no statistically significant associations between cancer-specific survival and variables such as sex, race/ethnicity, or neighborhood SES. Conclusions: Patients who started treatment within 30 days of diagnosis of metastatic kidney cancer experienced worse cancer-specific survival compared to those who started treatment between days 30-60 or after day 61 from time of diagnosis. The differences in survival may be a reflection of tumor biology and high- versus low-risk disease groups. Further research is warranted to identify which patients benefit from early versus delayed treatment initiation. [Table: see text]
Identification of novel actionable SNVs via targeted comprehensive genome profiling in patients with gallbladder and cholangiocarcinoma cancer.
Authors: Nirmal Vivek Raut, Mandar Bhonde, Chirantan Bose, Rakesh Chopra, Trupti Kad, Sangeeta Prajapati, Kanchan Hariramani, Fauzul Mobeen, Madhura Basavalingegowda, Sumit Haldar, Vatsal Mehra, Manoj Kumar Kumaran, Vikas Balasaheb Leelavati Jadhav, Sujit Krishnarao Joshi, Mithun Shah, Pankaj Manubhai Shah, Aravindan Vasudevan, Jayant Khandare, Gowhar Shafi
Journal: Journal of Clinical Oncology (2023)

e16006 Background: Liquid biopsy approach has paved the way for selecting targeted therapies. When the tissue is absent, the advent of comprehensive Next Generation Sequencing (NGS) using CcfDNA has further allowed significant advances in precision oncology by pinpointing rare, novel, and actionable alterations in oncogenes, tumor suppressor genes, and cellular signaling pathways. Methods: Retrospective NGS-based genome profiling was performed on ccfDNA (circulating cell-free DNA) samples from 11 patients using OncoIndx proprietary gene panel that targets exonic regions of 600 cancer-related genes. Illumina-compatible libraries were prepared by the target hybridization method and sequenced on Nextseq 2000 platform in a pair-end fashion. Variant calling was performed using an in-house developed bioinformatics pipeline. The 11 cases comprised 5 gallbladder and 6 cholangiocarcinoma patients. Results: We uncovered several novel mutations such as MTORK1452N, ERBB2H878Y, JAK1A634T, SMAD3R287W, IDH1R132C, PRKNK161N and FGFR2Y105C. Although ERBB2H878Y and IDH1R132C are known in cholangiocarcinoma, this is the first report of gallbladder cancer. In addition to SMAD3 and PARKIN, alterations were also observed in tumor suppressor proteins APC, BARD1, BRCA1/2, and GATA2. High genomic instability as demonstrated by HRD and LOH correlated with FGFR2, PRKN, and IDH1 mutations. FAT domain mutations in mTOR such as MTORK1452N are known to be responsive to rapamycin. Similarly, ERBB2H878Y is known to respond to rapamycin as well as a TKI. The FGFR2Y105C activating mutation has previously been reported in one case of atypical Crouzon Syndrome but has never been reported in cancer. This could have potential implications for the use of FGFR2 targeting agents in cholangiocarcinoma. IDH1R132C mutation is known in ~11% of cholangiocarcinoma patients, however, this alteration has not been reported in gallbladder cancer. This observation has therapeutic implications for the use of IDH1 inhibitors in gallbladder cancer based on its promising data in cholangiocarcinoma. Conclusions: We report, for the first-time novel and actionable SNVs in key oncogenes and tumor suppressors related to critical signaling pathways in a population of gallbladder and cholangiocarcinoma patients. The data strongly underscores the importance of comprehensive NGS-based in-depth assessment in gaining clinically viable therapeutic insights for patients.
Differential tumor gene expression profiling of obese and non-obese patients (pts) with prostatic adenocarcinoma (PC).
Authors: Vinay Mathew Thomas, Beverly Chigarira, Georges Gebrael, Nicolas Sayegh, Nishita Tripathi, Roberto Nussenzveig, Kamal Kant Sahu, Haoran Li, Gliceida Galarza Fortuna, Clara Tandar, Divyam Goel, James Brundage, Benjamin L. Maughan, Umang Swami, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2023)

5075 Background: Increased baseline body mass index (BMI) has been linked to poorer prostate cancer outcomes, including recurrence, reduced quality of life, and mortality (PMID: 21325564, 17211863). Herein, we sought to interrogate and validate the corresponding differences in tumor gene expression profiles of obese (Ob) vs. non-obese (N-Ob) pts with PC. Methods: In this IRB-approved retrospective study, eligibility criteria included histologically confirmed PC and available RNA sequencing results from treatment naïve primary prostate tissue from a CLIA-certified lab (either Tempus or Caris Life Sciences). Tempus cohort was used for interrogation and Caris for validation. Pts in each cohort were categorized into two groups: obese (BMI≥30) and non-obese (BMI&lt;30). BMI at the time of diagnosis of PC was used for analysis. The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were subjected to Gene Set Enrichment software analysis (GSEA) to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R v4.2. Results: Tempus cohort: n=60 (Ob =22, N-Ob=38); Caris cohort: n=50 (Ob=17, N-Ob=33). Both Tempus and Caris showed that Ob pts had an increased expression of the heme metabolism, androgen response, protein secretion, fatty acid, and bile metabolism pathways. N-Ob pts had a significantly higher expression of genes involved in the inflammation pathways (interferon-alpha &amp; TNF alpha pathways). Normalized enrichment scores are reported in the table. Differential gene set expression analysis in Ob vs. N-Ob pts with PC. Conclusions: Our study showed an upregulation of distinct genomic pathways in Ob pts with prostate cancer. For example, Ob pts with PC have tumors that depend more on androgen signaling, and N-Ob pts' tumors express increased inflammatory pathway genes that promote PC growth, invasiveness, and metastasis. After external validation, these hypothesis-generating data may provide the rationale for personalized therapy in men with PC. [Table: see text]
Pursuing cancer treatment across the US-Mexico border: Motivations and barriers.
Authors: Michael Brian LaPelusa, Haydee Cristina Verduzco-Aguirre, Fernando Cristobal Diaz, Fernando Aldaco, Enrique Soto Pérez de Celis
Journal: Journal of Clinical Oncology (2023)

e18575 Background: Healthcare utilization is a common reason for bidirectional travel across the US-Mexico border. We surveyed Mexican oncologists to understand why patients with cancer in the US and Mexico seek care outside their home country and what barriers they face. Methods: Approval was obtained from Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán´s IRB. Oncologists living in Mexican border states (Baja California, Sonora, Chihuahua, Coahuila, Nuevo León, and Tamaulipas) were identified from the Mexican Society of Oncology’s directory. Two hundred twenty-five participants were queried via e-mail with a REDCap survey designed by the investigators. Descriptive statistics were used to analyze responses. Results: Sixty-six respondents completed the survey, most of whom were medical (n = 24) or surgical oncologists (n = 24) who had practiced for &lt; 5 years (n = 31). Sixty (90.9%) respondents interacted with US-based patients who traveled to Mexico to receive care, most frequently due to inadequate health insurance (n = 45). Forty-eight (72.7%) respondents interacted with Mexico-based patients who traveled to the US to receive care, most frequently due to patient perception of superior care in the US (n = 38). Table 1 describes the reported reasons patients traveled across the border for cancer care. Twenty-nine (43.9%) respondents interacted with US-based patients who wanted to receive care in Mexico but could not, most frequently due to lack of financial resources (n = 17) or of a support system in Mexico (n = 10). Forty-three (65.2%) respondents interacted with Mexico-based patients who wanted to receive care in the US but could not, most frequently due of lack of financial resources (n = 43) or passport/visa issues (n = 14). Conclusions: According to Mexican oncologists, US-based patients travel to Mexico to receive cancer care primarily due to inadequate health insurance. In contrast, Mexico-based patients travel to the US primarily due to their perception that care in the US is of higher quality and because aspects of their care are unavailable in Mexico. Both US and Mexico-based patients face many barriers to receiving care outside their home country, which should be tackled to improve access to quality care in border region. [Table: see text]
A multicenter, single-arm, phase 2 study of surufatinib plus toripalimab for patients with advanced endometrial cancer.
Authors: Guangwen Yuan, Zhiping Li, Feng Ye, Bingzhong Zhang, Lin Shen, Yan-qiao Zhang, Xianjun Yu, Ying Cheng, Baorui Liu, Jianliu Wang, Xiaojun Chen, Jinghong Zhou, Haiyan Shi, Panfeng Tan, Songhua Fan, Michael Shi, Weiguo Su, Lingying Wu
Journal: Journal of Clinical Oncology (2023)

5609 Background: Several immunotherapy monotherapies, or combined with antiangiogenic inhibitors, have shown antitumor efficacy in endometrial cancer (EMC) and been approved by FDA. However, therapeutic options for EMC after failure of first-line treatment remain scarce in China. The open-label, multi-cohort, single-arm phase 2 study was performed to evaluate the efficacy and safety of the combination of surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) with toripalimab (an anti-PD-1 antibody) for Chinese patients (pts) with EMC after failure of one or more prior lines of systemic treatment. Methods: Pts with EMC who progressed or were intolerable after at least one prior line of systemic antitumor therapy were eligible and enrolled. They received 21-day cycles of surufatinib 250 mg orally, QD, plus toripalimab 240 mg IV, Q3W, until disease progression or reaching the maximum treatment duration with toripalimab of 24 months, or other protocol-specified criteria. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: From August 2020 to March 2022, 28 pts were enrolled and received the combination treatment (median duration: 4.6 months). Median age was 58 years (range: 50-71), and 22 (78.6%) pts were endometrioid adenocarcinoma at diagnosis. 9 (32.1%) pts had received ≥2 prior lines of therapy. As of 28 Dec 2022, the median follow-up duration was 16.8 months. Microsatellite status was available in 25 pts. 20 with mismatch repair-proficient (pMMR) and 5 with mismatch repair-deficient (dMMR) were determined. All 28 pts were evaluable with at least one post-baseline tumor assessment. Efficacy results were: confirmed ORR, 28.6% (8 partial response [PRs]); DCR, 82.1%; mDoR, 5.7 months; mPFS (95%CI), 5.4 months (2.7, 8.3); 12-month OS rate, 71.0%. Among pts with pMMR, the confirmed ORR was 25.0%; DCR was 85.0%; mDoR was 4.2 months; mPFS (95%CI) was 4.0 months (2.7, 8.3); 12-month OS rate was 75.4%. All pts experienced at least one treatment-emergent adverse event (TEAE), and 19 (67.9%) of them reported grade ≥3 TEAEs. The most common (≥5% pts) grade ≥3 TEAEs were hypertension (28.6%), aspartate aminotransferase increased (14.3%), alanine aminotransferase increased (10.7%), proteinuria (7.1%), Gamma-glutamyltransferase increased (7.1%) and malignant neoplasm progression (7.1%). No new safety signals were observed. Conclusions: Surufatinib plus toripalimab had a promising antitumor activity and a manageable safety profile in pts with EMC after failure of one or more prior lines of systemic therapy. Clinical trial information: NCT04169672 .
Effect on outcomes of toxicity-related dose reduction in TKI monotherapy or TKI-IO combination therapy for advanced renal cell carcinoma.
Authors: Giacomo Nuvola, David Humberto Marmolejo Castañeda, Veronica Mollica, Matteo Santoni, Victor Navarro Garces, Macarena González, Rafael Morales-Barrera, Joan Carles, Francesco Massari, Cristina Suárez
Journal: Journal of Clinical Oncology (2023)

4528 Background: Tyrosine kinase inhibitors (TKI) in monotherapy or TKI in combination with immunotherapeutic agents (IO) are standard of care fist-line treatment for advanced or metastatic renal cell carcinoma (RCC). Dose reduction due to toxicity is extremely frequently and represents an important clinical management issue, with frequent dose reduction, treatment suspension and change of schedule. We examined the outcomes of patient treated with TKI in monotherapy and in combination with immunotherapy (TKI-IO). Methods: We performed a retrospective analysis of clinical outcomes in patients with RCC treated with TKI (cohort 1) or TKI-IO (cohort 2) in Italian and Spanish institutions. A descriptive analysis was performed. Univariate logistic regression models were carried out to estimate the association between best response (CR or PR vs SD or PD) and type of TKI (monotherapy or combination therapy). Survival curves were estimated using the Kaplan-Meier method and were compared by the log-rank test. Cox proportional-hazard models were used to obtain hazard ratios (HRs) with 95%. Median follow-up was calculated using the reverse Kaplan-Meier method. Results: A total of 401 patients were divided in cohort 1 (329 patients) and cohort 2 (72 patients). Median Follow-up was 81.22 months in cohort 1 and 19.02 months in cohort 2. Most frequent toxicities that lead to dose reduction were mucositis (20.13%), Asthenia (16.88%) and Hand-foot syndrome (15.58%). Overall Response Rate was higher in patients that reduced dose, both in cohort 1 (48% vs 29%, p&lt;0.01) and cohort 2 (81% vs 40%, p&lt;0.01). In cohort 1 Progression Free Survival (PFS) was longer in patients with dose reduction (27.14 months vs 16.59 months) (HR 0.77 [0.6; 0.98]; p=0.04). Overall Survival (OS) was also improved (55 months vs 34.17) (HR 0.71 [0.53; 0.93]; p=0.01). In cohort 2, both PFS (39.13 months vs 41.3 months) (HR 0.63 [0.27; 1.48]; p=0.29) and OS (39.13 months vs 55.85 months) (HR 0.65 [0.26; 1.63]; p=0.29) did not statistically differ between patients that reduced dose and patients that did not reduce dose. Conclusions: TKI dose reduction due to toxicity seems to be related to improved outcomes, both in ORR and PFS/OS. ORR was statistically improved in both cohort 1 and cohort 2. PFS and OS in cohort 1 favoured patients that experienced dose reduction. PFS and OS in cohort 2 did not show a statistically significant difference, probably due to the short follow-up and small number of patients. However, outcomes seem to show a trend toward favouring patients that reduce dose.
Relationship between androgen biosynthesis linked to 3βHSD1 and resistance to radiotherapy: A germline biomarker for combined androgen blockade with radiation in high-risk prostate cancer.
Authors: Shinjini Ganguly, Zaeem M. Lone, Andrew Muskara, Jarell Imamura, Shilpa Gupta, Moshe Chaim Ornstein, Nima Sharifi, Omar Y. Mian
Journal: Journal of Clinical Oncology (2023)

e17084 Background: Around 50% of men with advanced prostate cancer (PCa) have at least one germline copy of the adrenal-permissive (1245C) HSD3B1 allele. This allele leads to higher levels of the steroid biosynthesis enzyme, 3β-hydroxysteroid dehydrogenase (3βHSD1). Inheriting this allele is linked to worse outcomes in men with advanced PCa. To determine if (1245C) HSD3B1 could be causing early resistance to combined androgen deprivation and radiotherapy in localized PCa, we studied its role in modulating radioresistance. Methods: PCa cell lines were used to investigate the reciprocal effects of 3βHSD1 knockdown and overexpression in intrinsically high and low 3βHSD1 lines, respectively. PCa xenografts were used to confirm the results in vivo. The connection between androgen receptor (AR) expression and elevated DNA Damage Response (DDR) gene expression was validated using transcriptomic data from 680 radical prostatectomy specimens The ability of enzalutamide, a non-steroidal anti-androgen, to restore radiosensitivity in 1245C expressing lines was interrogated in vitro and in vivo. Results: 1245C HSD3B1 expressing PCa lines displayed increased clonogenic survival after ionizing radiation. Effects were dependent on the 3βHSD1 substrate, DHEA, confirming intratumoral androgen metabolism was required for radioresistance. Resistant lines showed enhanced DNA double-strand break (DSB) repair and heightened DDR gene expression. PCa xenografts with 1245C HSD3B1 were similarly more resistant to radiation using murine models that faithfully mimic human adrenal physiology. A correlation between AR expression and increased DDR gene expression was confirmed in 680 patient samples. Enzalutamide pretreatment resulted in a decrease in DSB repair ability and re-sensitized 1245C HSD3B1 PCa cells to radiation. Conclusions: 1245C HSD3B1 fuels prostate cancer treatment resistance by elevating regional androgen biosynthesis from adrenal steroid precursors, leading to DDR gene overexpression and enhanced DNA DSB repair kinetics. This work supports clinical validation of biomarker informed selective intensification strategies, e.g., combined androgen blockade, for high-risk men with the 1245C HSD3B1 allele receiving curative intent radiotherapy.
IMPRESS-Norway: Improving public cancer care by implementing precision cancer medicine in Norway.
Authors: Aslaug Helland, Sigbjørn Smeland, Hege Russnes, Sigmund Brabrand, Katarina Puco, Pitt Niehusmann, Marte Grønlie Cameron, Egil Blix, Ase Haug, Irja Alida Oppdal, Daniel Heinrich, Sebastian Meltzer, Åsmund Flobak, Eli Sihn Steinskog, Cecilie Fredvik Torkildsen, Gro Live Fagereng, Astrid Dalhaug, Geir Olav Hjortland, Line Bjørge, Kjetil Tasken
Journal: Journal of Clinical Oncology (2023)

e15188 Background: Precision cancer medicine is evolving rapidly, with new drugs and biomarkers being developed. Advanced molecular diagnostics is a prerequisite for using some of the drugs, which might be approved on small or large subsets of patients. Drugs targeting a specific pathway or gene aberration, might be efficient in other tumour types harbouring the same molecular alteration, but not yet tried in randomized trials due to limited number of patients. This indicates that patients might benefit drugs that are on the market, not available for patients outside the existing indication. Methods: In this national-wide, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled into multiple parallel treatment cohorts. Patients with progressive disease on standard therapy, are eligible. Each cohort is defined by the patient’s tumour type, molecular profile, and study drug. Treatment outcome in each cohort is assessed by using a Simon two-stage-like ‘admissible’ monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Currently, 21 drugs are provided by six different pharmaceutical companies, and we are in process to acquire additional drugs for patients in this study. Molecular diagnostics with the TSO-500 gene panel are funded by the public health care system. In addition, patients included are offered analyses of circulating tumour DNA (ctDNA). The primary objective is to evaluate clinical benefit of treatment at 16 weeks of treatment, defined as complete response, partial response, or stable disease. Results: IMPRESS-Norway opened for accrual at April 1 st 2021. As of January 24, 2023, tumour cells from 791 patients with advanced cancer, have been analysed with TSO-500, and 662 patients had been discussed at the national molecular tumour board. 150 patients (23%) were allocated to therapy in different treatment-cohorts in IMPRESS-Norway, and 11% were referred to other ongoing clinical studies or early access programs. Extended and updated data and frequency of targetable molecular alteration will be presented. Conclusions: Patients with advanced cancer progressing on standard treatment are referred to treatment in IMPRESS-Norway after advanced molecular diagnostics. Genetic alterations indicating benefit of the drugs currently available in the study, are detected in 23% of 662 evaluated patients. Clinical trial information: NCT04817956 .